Cardiac ablation using microbubbles

ABSTRACT

In a cardiac ablation procedure, ultrasonic energy is emitted from an ultrasonic ablation device ( 28 ) and is focused on myocardial tissue ( 30 ) within the wall of the heart or within the wall of a blood vessel connected to the heart ( 10 ). Ultrasound attenuation of the cardiac tissue is selectively increased by introducing microbubbles into the circulatory system of the subject so that the microbubbles enter the coronary arteries and pass into the myocardial tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims benefit of U.S. Provisional PatentApplication Ser. No. 60/394,392, the disclosure of which is incorporatedby reference herein.

TECHNICAL FIELD

The present invention relates to medical procedures and devices forcardiac ablation and further relates to performing ultrasonic cardiacablation, or similar medical procedures, with microbubbles.

BACKGROND ART

Certain diseases can be treated by ablating tissues within the heart orin the vascular structures connected to the heart. Contraction or“beating” of the heart is controlled by electrical impulses generated atnodes within the heart and transmitted along conductive pathwaysextending within the wall of the heart. Diseases of the heart known ascardiac arrhythmias involve abnormal generation or conduction of theelectrical impulses. One such arrhythmia is atrial fibrillation or “AF”.Certain cardiac arrhythmias can be treated by deliberately damaging thetissue of the cardiac wall along a path crossing a route of abnormalconduction.

Cardiac arrhythmias such as AF have been treated by a procedure referredto as the “maze” procedure, in which a scar is formed by cutting intothe cardiac tissue of the atrium. The scar tissue forms a barrier topropagation of abnormal electrical signals. The surgical procedure isconducted so that the scar, and hence the barrier, isolates the focus ofthe arrhythmia. As described, for example, in co-pending, commonlyassigned U.S. patent application Ser. Nos. 09/815,863 (published as U.S.Application No. 20020002371), 09/905,227 (published as U.S. ApplicationNo. 2002.0065512) and 09/904,620 (published as U.S. Application No.20030013968), the disclosures of which are incorporated by referenceherein, it has been proposed to form a similar barrier by applyingultrasonic energy to the tissue of the heart wall so as to ablate themyocardial tissue along a loop extending around the site of thearrhythmia as, for example, extending around the ostium of a pulmonaryvein in the case of AF. As described in co-pending, commonly assignedU.S. Patent Application Serial Nos. 09/904,963 (published as U.S.Application No. 20020068885), 10/062,693 (published as U.S. ApplicationNo. 20020115990) and 10/131,755 (published as U.S. Application No.20030120270), the disclosures of which are also incorporated byreference herein, AF also can be treated by ablating myocardial tissuewhich extends from the heart wall along the pulmonary vein.

The medical procedure conducted to generate a scar can be performed byconventional surgery, but this entails all of the risks and expenseassociated with cardiac surgery. As described in Lesh, InternationalPublication WO 99/02096, the disclosure which is hereby incorporated byreference herein, the abnormal conduction routes in AF typically extendfrom the wall of the heart along the pulmonary veins. Therefore, AF canbe treated by ablating tissue in a ring around each pulmonary vein atthe juncture between the pulmonary vein and the heart. As described inthe '096 publication, such ablation can be performed by threading acatheter having a thermal ablation element at its distal tip into theheart so that the tip is lodged within the appropriate pulmonary vein.The catheter may bear a balloon which is inflated within the vein andwhich holds the catheter in place. The ablating element is then actuatedso as to apply heat in a region surrounding the ablating element. Incertain embodiments taught in the '096 publication, the ablating elementincludes a radio frequency (“RF”) emitting element which is carried onthe surface of the balloon. RF energy applied through the electrodeheats the tissue to a degree sufficient to cause death of the normaltissue and its replacement by scar tissue. Heating to this degree isreferred to herein as “ablation.” Typically, heating to about 60-80° C.is sufficient. Ablation of the pulmonary vein using RF energy can createa rough, disrupted surface on the interior of the vein. This or otherfactors can lead to stenosis of the pulmonary.vein or thrombosis, i.e.,formation of blood clots.

Another approach, described in Swartz et al., U.S. Pat. No. 5,575,766the disclosure of which is hereby incorporated by reference herein, isto introduce a catheter bearing a localized energy emitter such as anelectrode for application of RF energy at its distal tip into a heartchamber, such as the right or left atrium of the heart in the case ofAF. The physician then moves the catheter so that the tip, and thelocalized emitter traces the desired path. In AF, the desired pathtypically is a closed loop encircling the openings or ostia of thepulmonary veins. Tracing a precise path along the interior of a chamberin the heart of a living subject with the tip of a catheter involvesinherent practical difficulties. Although curved guide wires can beplaced within the catheter so that the catheter tip will tend to followthe guide wire as the physician moves it, the process is stilldifficult.

The last few years have seen the introduction of microbubbles ascontrast medium for use in diagnostic ultrasound imaging. These bubblesare used because they are highly attenuative, and serve to highlightvascular and highly perfused structures on brightness mode images. Manylaboratories are now exploring various therapeutic uses for mechanicallyintroduced microbubbles. With these developing avenues of research hascome a host of engineered bubbles, of various sizes, gaseous inclusionsand shell materials. Among other things, one of the parameters thatbubble designers are able to control is the half-life of these bubbleswithin the body before they dissolve.

In work unrelated to treatment of cardiac arrhythmias, Unger, U.S. Pat.No. 6,088,613, the disclosure which is hereby incorporated by referenceherein, describes a method of magnetic resonance imaging focusedsurgical and therapeutic ultrasound in conjunction with theadministration of a contrast medium. The contrast medium comprising gasfilled vesicles is used in conjunction with magnetic resonance imaging(MRI) on a patient requiring surgery, using the contrast medium whenconducting the MRI scan on the patient to identify the region of thepatient requiring surgery, and then applying ultrasound to the regionidentified.

Ultrasonic ablation within the heart and in the vascular structuresassociated with the heart has major advantages over competitivetechniques such as RF ablation. Among these advantages are thesignificantly greater attenuation of ultrasound energy in tissue than inblood, (unlike RF) allowing tissue heating without risk of bloodcoagulation, and the ability of ultrasound to deposit energy into tissueat depth, heating it directly, rather that relying on thermalconductivity as RF ablation does. While these advantages aresignificant, improvements to the conventional use of high intensityultrasound are still possible. One of the pitfalls of any energymodality in the body is the inability to target specific tissue types.The wavelength of the ultrasound energy typically used within the bodyallows the energy to be focused as described in the aforementionedco-pending, commonly assigned applications, which greatly improvesanatomical targeting. Techniques using focused ultrasonic energy arecommonly referred to by the acronym HIFU, for high-intensity focusedultrasound.

Tissue at the focal location is heated to a greater extent than tissueat other locations. Even with these improvements, however, it wouldstill be desirable to reduce the length of time required to achieve thetransmural lesions often required for cardiac ablations, and to furtherreduce the risk of damage to adjacent structures.

DISCLOSURE OF INVENTION

One aspect of the present invention provides a method for ablatingmyocardial tissue within the wall of the heart or within the wall of ablood vessel connected to the heart. In preferred methods according tothis aspect of the invention, microbubbles are supplied to thecirculatory system of a mammalian subject. The microbubbles perfuse themyocardial tissue of the subject. While the microbubbles are present inthe myocardial tissue, ultrasonic energy is applied to the wall of theheart or to the wall of a blood vessel connected to the heart. Themyocardial tissue having the microbubbles present therein is heated bythe ultrasonic energy and the myocardial tissue is then ablated.

Methods according to this aspect of the invention can be applied andused for pulmonary vein isolation or ablation, the treatment of AF, andfor common medical and surgical procedures involving ultrasound ablationof the heart or associated vascular structures.

Ultrasound attenuation of the myocardium is selectively increased withrespect to the adjacent venous tissue and with respect to other adjacentstructures by introducing microbubbles into the circulatory system sothat the microbubbles enter the coronary arteries and pass into themyocardial tissue. The myocardium is highly perfused tissue, receivingits blood supply from the coronary arteries. An injection ofmicrobubbles in the left ventricle (“LV”) results in the movement ofmicrobubbles into the coronary arteries through the aorta, andsubsequently perfusion of the myocardium with the microbubbles. Aninjection of these bubbles into the left atrium (“LA”) will also resultin the movement of the microbubbles through the mitral valve into theLV, out of the LV via the aortic root, and into the coronary arteries.An injection into the aorta, for example, at the openings of thecoronary arteries, or directly into a particular coronary artery, willprovide even more immediate passage of the microbubbles into themyocardial tissue to be ablated, and will minimize dilution of themicrobubbles.

Venous tissue is mostly connective, and not directly or highlyvascularized. Therefore, introduction of microbubbles into the bloodpassing to the heart via the coronary arteries increases the rate ofultrasonic absorption in myocardial tissues to a far greater degree thanin venous tissue. As discussed above, certain techniques which have beenproposed for treatment of AF direct ultrasonic energy into the wall ofthe pulmonary vein so as to ablate the myocardial muscular sheathes thatextend up the pulmonary veins from the heart. By selectively increasingthe rate of ultrasonic absorption of the myocardial tissue, introductionof microbubbles promotes selective heating of the muscular sheathes, andthus limits damage to the venous tissue. This, in turn, helps to avoidstenosis of the pulmonary veins resulting from the treatment. Statedanother way, heating of the venous tissue can cause the vein to rapidlyocclude. This is a potentially life threatening condition. The preferredtechniques according to the present invention can reduce the risk ofsuch vein stenosis.

Also, regardless of whether the ultrasonic energy is applied in theheart wall or in the vein wall, the enhanced absorption rate of thecardiac tissue allows faster ablation and reduces the total energy whichmust be delivered during the procedure, which in turn reduces the riskof collateral damage. Additionally, the enhanced absorptivity of themyocardial tissue reduces transmission of ultrasound through the cardiacwall to surrounding structures such as nerves, and thus further reducesthe risk of collateral damage. Moreover, by reducing the total energywhich must be delivered, the microbubbles reduce the waste heatdissipated by the ultrasonic applicator. Certain ultrasonic applicatorsdisclosed in the applications mentioned above use a balloon filled withan aqueous liquid surrounding a piezoelectric ultrasonic applicator. Thefluid is circulated into and out of the balloon to maintain the balloonat a temperature of the balloon below the level of coagulation of theblood, (60-65° C.). By reducing the amount of energy which must bedelivered, the need for such circulation can be reduced or eliminated,greatly simplifying the procedure and reducing the cost of the ablationsystem and catheter.

The timing of the high power sonication can be determined through theuse of intracardiac or other ultrasound imaging. Currently, much of thepulmonary vein isolation procedure is guided by intracardiac ultrasound,for example, with an imaging catheter in the right atrium (“RA”) lookingtoward the LA and the pulmonary veins. An imaging procedure optionallycan be used in methods according to this aspect of the invention. As themyocardium of the LA is observed to brighten in the diagnostic image,indicating that the microbubbles have perfused the myocardium, theultrasonic energy can be applied.

The microbubbles chosen for this type of selective ablation wouldideally be short-lived, with an engineered half-life of less than onetrip around the body. As is known in design of microbubbles for use asultrasonic imaging contrast agents, the half-life of microbubbles iscontrolled by factors such as the composition of the materialsurrounding the gas in the microbubble, commonly referred to as the“shell” of the microbubble, and by the diffusion rate of the gas withinthe microbubble. For example, common microbubbles used as ultrasoniccontrast agents contain carbon dioxide surrounded by a protein micelle.By designing bubbles to have the proper half-life, bubbles introduced tothe arterial system before the ablation of one pulmonary vein would notbe present in the LA (in the blood returning from the lungs) as the nextsonication was delivered by an ablation device. Thus, the half-life ofthe microbubbles preferably should be selected so that it is sufficientto survive the relatively brief interval required for movement of themicrobubbles from the site of administration (the LA, LV, aorta orcoronary arteries) into the myocardial tissue but not sufficient tosurvive a complete passage through the systemic circulation, the heartand the pulmonary circulation back into the LA. Timing in this mannerwould maintain the advantage that ultrasound has in being able topenetrate blood relatively unabated, depositing energy only in thetissue.

A further aspect of the invention provides a kit for ablating myocardialtissue of a mammalian subject. The kit according to this aspect of theinvention desirably includes an ultrasonic ablation device adapted toapply ultrasonic energy to the wall of the heart or to a blood vesselconnected to the heart, together with microbubbles adapted foradministration into the circulatory system of the subject. Theultrasonic ablation device may be carried on a catheter structure whichextends into or through the LA or LV in operation. The catheterstructure may include a lumen having an opening that communicates withthe LA or LV that allows for microbubbles to be dispersed.Alternatively, the kit may include a separate microbubble catheteradapted for insertion into the heart, in the aorta, or into a coronaryartery, at a position that is not in close proximity to the ultrasonicablation device. The kit optionally may include an imaging device.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagrammatic view depicting one embodiment of the invention.

FIG. 2 is a diagrammatic view of a further embodiment of the invention.

FIG. 3 is a diagrammatic view of yet another embodiment of theinvention.

BEST MODE FOR CARRYING OUT THE INVENTION

FIG. 1 shows a method for performing cardiac ablation in accordance withone embodiment of the present invention. The method includes the use ofan ultrasonic ablation device 28. Device 28 preferably is a deviceaccording to the aforementioned co-pending, commonly assigned U.S.patent application Ser. Nos. 09/905,227, 09/904,963 and 09/904,620, andincludes an ultrasonic emitter together with a reflector or lens forfocusing the energy emitted from the emitter onto a region of tissue tobe ablated. Device 28 desirably is mounted on the distal end 29′ ofcatheter referred to herein as the device catheter. The proximal end 29″of the device catheter is connected to a source of excitation energy(not shown) from the ultrasonic device. The apparatus further includes amicrobubble catheter 54, and an intracardiac or ultrasound imagingdevice 48. The distal end of the ultrasonic ablation device 28′ is movedinto the heart 10 by a physician. The physician then moves the distalend 29′ of the device catheter so that the ultrasonic ablation device 28is positioned in proximity to myocardial tissue to be ablated 34 in theleft atrium 22, while the proximal end of the device catheter 29″,remains outside the patient's body. The distal end 24 of the microbubblecatheter 54 is positioned in the aorta 26. The proximal end 40 of themicrobubble catheter 54 is connected by tubing 42 to a pump 44. The pump44 facilitates the movement of the microbubbles from a microbubblesupply 46 to the microbubble catheter 54. Pump 44 may be integrated withmicrobubble supply 46. For example, the pump may be a manually-operatedor mechanically-operated syringe. Typically the microbubbles areprovided as a slurry in a liquid carrier acceptable for introducing intothe body. Microbubbles enter the aorta 26 by exiting the lumen of themicrobubble catheter 54 at a portal 52 at the distal end of themicrobubble catheter 24. The natural blood flow of the heart 10 feedsthe microbubbles into coronary arteries 32 (see FIG. 2), whichsubsequently feeds blood to the myocardial tissue 30.

An imaging catheter 38 is positioned in the right atrium 14 to looktoward the left atrium 22 and pulmonary veins 12′, 12″. The imagingcatheter 38 may be positioned in the right atrium 14 via the superiorvena cava 36, or in any position desired by the physician to observe aregion of the heart or myocardial tissue to be ablated. In such aposition, a site to be ablated within the left atrium 22 or pulmonaryveins 12′, 12″ may be scanned with the imaging catheter 38 and viewed bya physician with an intracardiac or other ultrasound imaging device 48.When perfused with microbubbles, the myocardium 30 of the left atrium 22is observed to brighten on the imaging device 48. The presence ofmicrobubbles in the region to be ablated 34 signals that the ultrasonicenergy can be applied from the ultrasonic ablation device 28.

The physician actuates the energy source connected to the ultrasonicablation device 28, so that the device emits energy which impinges onthe tissue to be ablated.

The ultrasound attenuation of the myocardial tissue 30 is selectivelyincreased with respect to the adjacent tissues by the microbubblespresent in the myocardial tissue 30.

The apparatus and method according to the embodiment of FIG. 2 are thesame as discussed above with reference to FIG. 1, except that themicrobubbles are administered directly into a coronary artery 32. Themyocardial tissue 30 is highly perfused, receiving its blood supply fromthe coronary arteries 32. In further variants of the invention, themicrobubbles may be introduced into the circulatory system of thesubject at a multiplicity of sites. For example, an injection ofmicrobubbles in the left ventricle 18 results in the dispersion ofmicrobubbles into the coronary arteries 32 via the aorta 26, andperfusion of the myocardium 30 with the microbubbles. An injection ofmicrobubbles may also be performed into the left atrium 22 as discussedbelow with reference to FIG. 3.

The apparatus and method of FIG. 3 are the same as discussed above withperspective to FIG. 1, except that in the apparatus of FIG. 3,microbubble catheter structure 129 includes a lumen 130 with a port 131adjacent to the distal end of the device catheter. Here again, theultrasonic ablation device 28 is mounted adjacent to the distal end ofthe device catheter. Thus, when the physician positions the ablationdevice within the LA, adjacent to the tissue to be ablated, port 131 isalso disposed in the LA. Lumen 130 is connected at the proximal end ofthe device catheter to a pump 44 and microbubble supply 46 as discussedabove. Thus, in this embodiment, the device catheter performs themicrobubble delivery function, and a separate microbubble catheter isnot required. Release of microbubbles from the portal 131 of themicrobubble catheter structure 129 deposits microbubbles into the leftatrium 22. Natural blood flow moves the microbubbles through the mitralvalve 20 and into the left ventricle 18. From the left ventricle 18microbubbles enter the aorta 26, followed by entry into coronaryarteries 32 (see FIG. 2) and then into myocardial tissue 30.

Microbubble composition and the composition of the shell of themicrobubble affects the half-life of the microbubbles, which in turnaffects the ultrasonic absorption of tissues containing themicrobubbles. Preferably, during the ablation procedure, microbubblesare present in the tissue to be ablated but not in adjacent structuresof the body that lie in the path of the ultrasonic energy. The presenceof microbubbles in myocardial tissue increases the rate of ultrasonicabsorption in myocardial tissues compared to other tissues, such asvenous tissue. Preferably, the half-life of the microbubbles is short,with an engineered half-life of less than one trip around the body.Thus, the half-life of the administered microbubbles would be sufficientto survive the relatively brief interval required for movement from thesite of administration (such as the left atrium 22, left ventricle 18,aorta 26, or coronary artery 32) into the myocardial tissue 30, but notsufficient to survive a complete travel through the systemic circulationof the body.

In a further variant of the procedure and apparatus discussed above, theimaging catheter 38 and imaging device 48 can be omitted. In thisvariant, the ultrasonic emitter is actuated at a predetermined timeafter administration of the microbubbles. This time is selected so thatit corresponds to the time required for the microbubbles to pass fromthe site of administration to the tissue to be ablated.

A kit for performing the procedures discussed above desirably includessome or all of the apparatuses discussed above, together with themicrobubbles.

INDUSTRIAL APPLICABILITY

The invention has applicability in the medical industry.

1. A method of ablating myocardial tissue within the wall of the heartor within the wall of a blood vessel connected to the heart comprising:(a) supplying microbubbles to the circulatory system of a mammaliansubject so that the microbubbles perfuse the myocardial tissue of thesubject; and (b) while the microbubbles are present in the myocardialtissue, applying ultrasonic energy to the wall of the heart or to thewall of a blood vessel connected to the heart so that myocardial tissuehaving microbubbles present therein is heated by the ultrasonic energyand ablated.
 2. A method as claimed in claim 1 wherein said step ofsupplying microbubbles is performed by introducing the microbubbles intothe LA or LV.
 3. A method as claimed in claim 2 wherein said step ofapplying ultrasonic energy is performed by actuating an ultrasonictransducer carried on a catheter structure extending into or through theLA or LV, and wherein said step of supplying microbubbles is performedby administering said microbubbles through said catheter assembly.
 4. Amethod as claimed in claim 1 wherein said step of supplying microbubblesis performed by introducing the microbubbles into the aorta.
 5. A methodas claimed in claim 1 wherein said step of supplying microbubbles isperformed by introducing the microbubbles directly into a coronaryartery supplying blood to the portion of myocardial tissue to beablated.
 6. A method as claimed in claim 1 further comprising the stepof determining when the microbubbles are present in the myocardialtissue to be ablated by ultrasonic imaging of the myocardial tissue. 7.A kit for ablating myocardial tissue of a mammalian subject comprising:(a) an ultrasonic energy application device adapted to apply ultrasonicenergy to the wall of the heart or to a blood vessel connected to theheart; and (b) microbubbles adapted for administration within thecirculatory system of the subject.
 8. A kit as claimed in claim 7further comprising a catheter adapted for insertion into the aorta orinto a cardiac artery for administering said microbubbles.
 9. A kit asclaimed in claim 7 wherein said ultrasonic energy application device isadapted to administer ultrasonic energy to the wall of a blood vesselconnected to the heart.
 10. A kit as claimed in claim 9 wherein saidultrasonic energy application device is adapted to administer ultrasonicenergy to the wall of a pulmonary vein.
 11. A kit as claimed in claim 7wherein said ultrasonic energy application device is adapted toadminister ultrasonic energy to the wall of the heart.
 12. A kit asclaimed in claim 7 wherein said ultrasonic energy device includes acatheter structure and said catheter structure extends into or throughthe LA or LV when the device is in an operative condition, and whereinsaid catheter structure includes a lumen having an opening, said openingcommunicating with the LA or LV when the device is in said operativecondition, whereby the microbubbles can be administered by way of saidcatheter structure.